Table 3.
Patients in the study
| Subject | Clinical information | Clinical tests ordered | Primary/possibly related variants from research exome | Secondary findings from research exome | Diagnosis by research ES | Diagnosis by clinical test |
|---|---|---|---|---|---|---|
| P02 | Moderate to severe BLSNHL | OtoGenome: positive (pathogenic: GJB2 comp. het. c.-23+1G>A; c.71G>A [p.Trp24X]) | Positive: GJB2: pathogenic, c.71G>A (pTrp24X); MYO15A: pathogenic, c.3311dupG (p.Glu1105Terfs) and pathogenic, c.5925G>A (p.Trp1975Ter) on the same allele | MA carrier: GNE, c.2179G>A (p.Val727Leu) | No (did not identify intronic variant) | Yes |
| P05 | Bilateral mixed HL, hypoplastic R cochlear nerve, ectopic atrial tachycardia-mediated cardiomyopathy, short stature | SNP array: normal; SHOX: normal; ES (Baylor College of Medicine): initially negative. Updated report in 2017 (AMMECR1: likely pathogenic, c.524_528dupGGCTT [p.F177fs]) | Inconclusive: LOXHD1: VUS, c.2469C>A (p.Asn823Lys); MYH14: VUS, c.3506G>A (p.Arg1169Gln); OTOF: VUS, c.2034_2042dupTGCCGGGGA (p.Asp681_Leu682insAlaGlyAsp) | None | No | No, but clinical reanalysis reported a likely pathogenic result in 2017 |
| P10 | BLSNHL | SNP array: inconclusive. 15q13.1del OtoGenome V2: inconclusive (SLC17A8: VUS, c.547G>A [p.Gly183Arg]) | Inconclusive: LRTOMT: VUS, c.-704+1G>A | IMA: TNNI3, c.485G>A (p.Arg162Gln); IMA: LDLR, c.1003G>A (p.Gly335Ser); carrier: AGL, c.664+3A>G; carrier: BTD, c.1330G>C (p.Asp444His) | No | No |
| P12 | Mild BLSNHL | SNP array: normal; OtoGenome V2: inconclusive (TECTA: VUS, c.4304C>T [p.Arg1462Cys]; USH1C: likely pathogenic, c.2167C>T [p.Gln723X]; LOXHD1: VUS, c.5437G>A [p.Val1813Ile]; CPR98: VUS, c.7867G>A [p.Glu2623Lys]) | Inconclusive: TECTA: VUS, c.4304C>T (p.Arg1462Cys) | Carrier: USH1C, c.2167C>T (p.Gln723Ter); carrier: G6PD, (comp. het.): c.202G>A (p.Val68Met); c.376A>G (p.Asn126Asp) | No | No |
| P22 | Mild BLSNHL, myopia | SNP array: normal; OtoGenome V2: inconclusive (POU4F3: VUS, c.103T>C [p.Cys35Arg]) | None | Carrier: MUTYH, c.1187G>A (p.Gly396Asp) | No | No |
| P29 | Moderate to profound BLSNHL | SNP array: normal; OtoGenome V2: inconclusive (TMPRSS3: VUS, c.1152G>T [p.Met384Ile]) | Inconclusive: TMPRSS3: VUS, c.1152G>T (p.Met384Ile) | IMA: RHO, c.491C>T (p.Ala164Val); carrier: BTD, c.1330G>C (p.Asp444His) | No | No |
| P47 | Conductive HL, thin upper lip, prominent maxilla, small size | SNP array: normal | Positive: EFTUD2: pathogenic, c.764dup (p.Cys256Valfs*6) | None | Yes | No (gene not on OtoGenome) |
| P50 | Mild to moderate BLSNHL, lip pits, autism | SNP array: normal; BAC array: normal; IRF6: negative; fragile X: normal | Inconclusive: OTOG: VUS, c.4877C>T (p.Pro1626Leu) | Carrier: DNAH5, c.4348C>T (p.Gln1450Ter); carrier: DHCR7, c.461C>G (p.Thr154Arg); carrier: ABCA4, c.5882G>A (p.Gly1961Glu) | No | No |
| P52 | Profound BLSNHL, all growth parameters >95th percentile | SNP array: normal; OtoGenome V2: positive (SLC264A4; pathogenic, hom. c.2089+1G>A) | Positive: SLC26A4: pathogenic, hom. c.2089+1G>A | None | Yes | Yes |
| P53 | Moderate to profound BLSNHL, vestibular disorder | SNP array: normal; OtoGenome V2: negative | Inconclusive: OTOG: VUS, c.433G>A (p.Gly145Ser) | Carrier: PLEC, c.1141C>T (p.Gln381Ter); carrier: PYGM, c.1094C>T (p.Ala365Val) | No | No |
| P56 | Moderate to profound BLSNHL, family history of syndromic HL | SNP array: normal | Inconclusive: DFNB31: VUS, c.191C>A (p.Ala64Asp) | None | No | No |
| P58 | Moderate to severe BLSNHL, mild dystopia canthorum, hemangioma on L anterior leg | None | Positive: GJB2: pathogenic, hom. c.35delG (p.Gly12Valfs*2) | Carrier: IDUA, c.208C>T (p.Gln70Ter); carrier: FLG, c.1501C>T (p.Arg501Ter); carrier: SEPN1, c.943G>A (p.Gly315Ser) | Yes | No (none performed, but probably would have been detected if OtoGenome had been performed) |
| P60 | Severe to profound BLSNHL | None | None | Carrier: CFTR, c.1520_1522delTCT (p.Phe508delPhe) | No | No (one performed) |
| P63 | Dysmorphia (telecanthus, posteriorly rotated ears), mild to moderate BLSNHL, hypotonia, sacral dimple, motor delays, abnormal eye movements, tapetoretinal degeneration identified on MRI | SNP array: normal; PAX3 seq.: normal | Positive: PEX1: pathogenic, comp. het., c.3379_3380in (p.Arg1127Profs*9); c.2528G>A (p.Gly843Asp) | Carrier: ENAM, c.1259_1260insAG (p.Pro422Valfs); carrier: GJB2, c.35delG (p.Gly12Valfs) | Yes | No (gene not on OtoGenome) |
| P64 | Mild to moderately severe BLSNHL, hip dysplasia | SNP array: normal; OtoGenome V2: inconclusive (LOXHD1: VUS, c.1570C>T [p.Arg524Cys]) | Inconclusive: LOXHD1: VUS, c.1570C>T (p.Arg524Cys) | Carrier: GALT, c.940A>G (p.Asn314Asp) | No | No |
| P65 | Moderate BLSNHL, developmental delay, speech delay | SNP array: normal; OtoGenome V1: inconclusive (COL11A2: VUS, c.3932A>G [p.Asn1311Ser]; KCNQ4: VUS, c.1325T>C [p.Met442Thr]; MYO3A: VUS, c.2275A>T [p.Asn759Tyr]; TJP2: VUS, c.1144_1146delATT [p.Ile382del]) | Inconclusive: COL11A2: VUS, c.3932A>G (p.Asn1311Ser) | None | No | No |
| P66 | Severe BLSNHL | None | Positive: GJB2: pathogenic, hom. c.35delG (p.Gly12Valfs*2) | None | Yes | No (none performed, but probably would have been detected if OtoGenome had been performed) |
| P69 | Severe to profound BLSNHL | SNP array: normal; OtoGenome V2: inconclusive (LOXHD1; VUS, c.1570C>T [p.Arg524Cys]) | Inconclusive: LOXHD1: VUS, c.1570C>T (p.Arg524Cys); OTOG: VUS, c.952G>A (p.Ala318Thr) | Carrier: GALT, c.940A>G (p.Asn314Asp) | No | No |
| P74 | Moderate BLSNHL, Asperger’s syndrome | None | Inconclusive: USH2A: VUS, c.8200G>A (p.Val2734Met) | Carrier: BTD, c.1330G>C (p.Asp446His) | No | No |
| P79 | Unilateral (L-sided) severe SNHL, R ear tag | EYA1 seq. del./dup.: negative; SIX1 seq.: negative | None | Carrier: CFTR, c.1520_1522delTCT (p.Phe508delPhe); carrier: GALT, c.940A>G (p.Asn314Asp) | No | No |
| P80 | Severe to profound BLSNHL | None | Inconclusive: MARVELD2: VUS, c.1660G>A (p.Val554Ile) | None | No | No |
| P81 | Moderate BLSNHL | SNP array: normal; CHOP HL panel: negative | Inconclusive: COL9A2: VUS, c.2059A>G (p.Lys687Glu); OTOG: VUS, c.1876C>T (p.Arg626Trp) | None | No | No |
| P86 | Profound BLSNHL | SNP array: normal; OtoGenome V2: positive pathogenic; GJB2: hom. c.35delG (p.Gly12fs) | Positive: GJB2: pathogenic, hom. c.35delG (p.Gly12Valfs*2) | Adult MA: BRCA1, c.5503C>T (p.Arg1835Ter); carrier: GALT, c.940A>G (p.Asn314Asp) | Yes | Yes |
| P90 | Moderate to profound BLSNHL | SNP array: normal; fragile X: normal; Waardenburg/MITF and SOX10 seq. del./dup.: negative; OtoGenome V2: inconclusive (DFNB31: VUS, c.2569C>T [p.Gln857X]; MYO15A: VUS, c.7367C>G [p.Ala2456Gly]; USH2A: VUS, c.3043C>T [p.His1015Tyr]) | Positive: SMPX: pathogenic, c.133-1G>A | Carrier: PKHD1, c.5448_5449insAT (p.Val1817Metfs*6) | Yes | No (gene not on OtoGenome) |
| P92 | Mild to moderate BLSNHL | SNP array: normal; OtoGenome V2: inconclusive (LOXHD1: pathogenic, c.4480C>T [p.Arg1494X]; MYO15A: VUS, c.4848C>G [p.Phe1616Leu]; WFS1: VUS, c.1297G>A [p.Ala433Thr]; LOXHD1: likely benign; revised to VUS, c.4526G>A [p.Gly1509Glu]) | Positive: LOXHD1: comp. het., pathogenic, c5085+847_5085+859dup (p.Glu599Leufs*23); c.4480C>T (p.Arg1494*) | None | Yes | No (only 1 LOXHD1 variant, c4480C>T [p.Arg1494X], was reported in the clinical report) |
| P93 | Moderate to severe BLSNHL | SNP array: normal; OtoGenome V2: inconclusive (GJB2: pathogenic, -23+1G>A; STRC: likely pathogenic, 3307-5T>G; HGF: VUS, c.983G>T [p.Arg328Leu]) | Inconclusive: CACNA1D: VUS, c.2310C>A (p.Ile770=); HGF: VUS, c.983G>T (p.Arg328Leu) | Carrier: MUTYH, c.1228_1229insGG (p.Glu410Glyfs) | No | No |
| P95 | BLSNHL | None | Inconclusive: LOXHD1: VUS, c.3962G>C (p.Gly1321Ala); ADGRV1: VUS, c.17992G>A (p.Val5998Met); OTOF: VUS, c.5938G>T (p.Ala1980Ser) | Carrier: HBB, c.20A>T (p.Glu7Val) | No | NA |
| P101 | Mild to moderate BLSNHL, macrocephaly, anklyglossia, frenotomy, R lower lip hemangioma | OtoGenome V2: negative | Positive: SIX1: pathogenic, c.460A>T (p.Lys154*) | Carrier: CFTR, c.3454G>C (p.Asp1152His) | Yes | No (gene not on OtoGenome) |
| P104 | BLSNHL | None | Inconclusive: TECTA: VUS, c.3854G>C (p.Cys1285Ser); OTOG: VUS, c.5381T>C (p.Leu1794Pro) | None | No | NA |
| P109 | Profound BLSNHL, elevated W-index | SNP array: normal; Waardenburg: negative | Inconclusive: TMC1: VUS, c.938T>C (p.Phe313Ser); TMC1: VUS, c.624C>A (p.Ser208Arg); CDH23: VUS, c.1583G>A (p.Arg528His); MYH9: VUS, c.3340T>C (p.Ser1114Pro) | None | No | No |
| P111 | BLSNHL | OtoGenome V2: inconclusive (CDH23: VUS, c.7517G>A [p.Arg2506Gln]; MYO6: VUS, c.2716T>C [p.Ser506Pro]; POU4F3: VUS, c.403C>T [p.Pro135Ser]) | Inconclusive: MYO6: VUS, c.2716T>C (p.Ser906Pro); CDH23: VUS, c.7517G>A (p.Arg2506Gln); POU4F3: VUS, c.403C>T (p.Pro135Ser) | Carrier: ALPL, c.571G>A (p.Glu191Lys); carrier: SERPINA1, c.1096G>A (p.Glu366Lys) | No | No |
| P112 | Mild to moderate BLSNHL with a conductive component | SNP array: inconclusive, 22q11.21dup; OtoGenome V2: inconclusive (STRC: pathogenic, c.4701+1G>A; STRC: VUS, c.4917_4918delinsCT [p.Leu1640Phe]; OTOF: VUS, c.154G>A [p.Val52Met]; PCDH15: VUS, c.2102C>T [p.Ala701Val]) | Positive: STRC: comp. het., pathogenic, c.4918C>T (p.Leu1640Phe) and c.4701+1G>A; OTOF: VUS, c.154G>A (p.Val52Met); PCDH15: VUS, c.2102C>T (p.Ala701Val) | None | Yes | No (only 1 STRC variant called pathogenic in the clinical report) |
| P118 | BLSNHL | SNP array: inconclusive, 1q24.2 del; SLC19A2 seq.: negative; OtoGenome V2: inconclusive (ACTG1: VUS, c.521C>G [p.Ala174Gly]) | Inconclusive: ACTG1: VUS, c.521C>G (p.Ala174Gly) | Carrier: PAH, c.1139C>T (p.Thr380Met); carrier: ATM, c.788delT (p.Tyr264Ilefs) | No | No |
| P124 | Bilateral mixed HL, developmental delay, learning disability, dysmorphic features | Array CGH: normal; FISH 22q: normal, karyotype: normal; fragile X: negative | None | NA | No | No |
| P128-1 | Mild BLSNHL with conductive component in R ear, cupped ears with bilateral small preauricular pits, deep R branchial sinus cleft | None | Positive: EYA1: pathogenic, c.1615G>T (p.Glu539X) | Carrier: DHCR7, c.964-1G>C | Yes | No (none performed, but probably would have been detected if OtoGenome had been performed) |
| P128-2 | Bilateral mixed HL | None | Positive: EYA1: pathogenic, c.1615G>T (p.Glu539*) | Carrier: GLDC, c.499G>T (p.Glu167Ter) | Yes | No (none performed, but probably would have been detected if OtoGenome had been performed) |
| P130 | Mild BLSNHL | SNP array: normal; fragile X: negative; Waardenburg: negative; OtoGenome V2: inconclusive (GJB2: pathogenic, c.101T>C [p.Met34Thr]; MYO15A: pathogenic, c.8714-1G>A; ESPN: VUS, c.1048C>T [p.Pro350Ser]; TRIOBP: VUS, c.4666G>A [p.Glu1556Lys]) | Inconclusive: GJB2: pathogenic, c.101T>C (p.Met34Thr); MYO15A: pathogenic, c.8714-1G>A; ESPN: VUS, c.1048C>T (p.Pro350Ser) | Carrier: FANCC, c.356_360delCTCAT (p.Ser119Tyrfs) | No | No |
| P145 | Unilateral R SNHL, constipation, intestinal pseudo-obstruction, R auditory neuropathy, autism spectrum disorder | None | None | Carrier: SERPINA1, c.863A>T (p.Glu288Val) | No | NA |
| P146 | Mild to moderate BLSNHL | CHOP HL panel: negative | Positive: OTOG: pathogenic, hom. c.2500C>T (p.Gln834*) | Carrier: PAH, c.194T>C (p.Ile65Thr) | Yes | No (gene not on OtoGenome) |
| P149-1 | Moderate to severe BLSNHL | CHOP HL panel: negative | Positive: MYO15A: pathogenic, comp. het., c.5055dup; c.1721G>C and c.6580>T (p.Asp1686Glnfs*13;p.Arg574Pro;p.Arg2194Trp) | None | Yes | No (but probably would have been detected if Otogenome had been performed) |
| P149-2 | Moderate to severe BLSNHL | CHOP HL panel: negative | Positive: MYO15A: pathogenic, comp. het., c.5055dup, c.1721G>C and c.6580>T (p.Asp1686Glnfs*13;p.Arg574Pro;p.Arg2194Trp) | Carrier: SLC25A13, c.468+1G>C | Yes | No (but probably would have been detected if Otogenome had been performed) |
| P165 | BLSNHL (L: severe to profound; R: mild to moderate) | None | Inconclusive: CDH23: VUS, c.8248G>A (p.Val2750Met) | None | No | NA |
| P178 | Mild BLSNHL, axonal motor neuropathy, tarsal coalition, nephrolithiasis | Distal motor neuropathy panel (prevention genetics): negative | Positive: COCH: pathogenic, c.1625G>T (p.Cys542Phe) | None | Yes | No (but probably would have been detected if OtoGenome had been performed) |
BAC bacterial artificial chromosome, CGH comparative genomic hybridization, comp. het. compound heterozygous, del. deletion, dup. duplication, FISH fluorescence in situ hybridization, hom. homozygous, IMA immediately medically actionable, L left, MA medically actionable, MRI magnetic resonance imaging, NA not available, R right, seq. sequencing, VUS variant of uncertain significance, ES exome sequencing